Glucocorticoids are important steroids for intermediary metabolism, immune function, musculoskeletal and connective tissue as well as the brain. The importance of the glucocorticoids is best understood in patients with glucocorticoid deficiency. In such patients, the one-year survival rate was only 20% in the 1950s before the availability of glucocorticoid replacement therapy. The major use of glucocorticoids in clinical practice began, however, with their use in the treatment of rheumatoid arthritis in the 1940s. Both natural and synthetic glucocorticoids have been employed in the management of a wide variety of conditions and they play a crucial part of many emergency treatments involving allergic and inflammatory disorders.
The endogenous glucocorticoids are steroids predominantly produced in the adrenal cortex. The main glucocorticoid in the body is cortisol. The production and secretion of cortisol is governed by a complex and highly efficient system that includes the hypothalamus, pituitary and the adrenal glands i.e. hypothalamic-pituitary-adrenal axis (HPA). Cortisol secretion has a circadian release rhythm with peak values in early morning and trough values at midnight. The HPA axis is also activated by several physical and psychological stressors. Thus, under stress conditions, such as physical activity, fever, surgery or mental stress, the serum cortisol concentration is increased.
Adrenocortical deficiency results in a number of complex symptoms that results from deficiency of adrenocortical hormone activity. It may be of a primary type as a result of a disease in the adrenal cortex, a secondary (central) type due to the specific pathology in the hypothalamus and/or the pituitary gland, or a tertiary type due to a suppressed HPA axis after long-term high dose glucocorticoid treatment.
The onset of adrenocortical insufficiency may vary from insidious to an acute life-threatening situation with severe salt and water deficit, which leads to shock and death if not treated fast and adequately.
Therapy of e.g. acute adrenal crisis requires that the one or more glucocorticoids quickly enter (are absorbed) into the systemic circulation at a therapeutically effective concentration interval (therapeutic window). Although a number of various glucocorticoid-containing pharmaceutical compositions already are on the market, most of these are not suitable for the treatment of a disorder requiring acute glucocorticoid therapy as they either result in a too slow appearance in the systemic circulation (e.g. conventional tablets) or in a too low, if any, glucocorticoid serum level (many glucocorticoid-containing pharmaceutical compositions are intended for local treatment e.g. in the nose or on the skin).
There are today two ways of administering glucocorticoids in medical emergencies. One is the parenteral route where an intravenous (IV) infusion has to be set up or a deep intramuscular (IM) injection has to be given. However, one disadvantage of this administration is that an IV route can be challenging to establish particularly in patients with compromised peripheral circulation. Furthermore, parenteral administration requires qualified personnel and is therefore limited to well-crewed ambulances and in-hospital settings.
The other administration route is traditionally by oral administration using a dissolvable betamethasone tablet in water. This route is mainly used in outpatient clinics and for patient self-medication. However, the disadvantages are the considerable lag-time when preparing the solution and the time from intake until a significant serum level of the drug is obtained. The maximum plasma concentration (Cmax) is usually reached within 1 to 3 hours after administration (Tmax) It is also well known that the onset of intestinal absorption cannot be earlier than 0.5 hour for these oral immediate release products of a rapidly dissolved and rapidly absorbed drug (a class I drug according to the FDA's Biopharmaceutics Classification System), the gastric emptying being very variable both in the fasted and fed state. Furthermore, it is mandatory that the patient is conscious and has unaffected ability to swallow the solution since a weak gastrointestinal motility results in a further delay in gastric emptying and reduced intestinal absorption (both rate and extent).
Examples of such cumbersome oral administrations are obtained in patients with acute laryngitis, patients with severe distress due to breathlessness, children with croup or severe angioedema, and in patients with gastroenteritis where gastrointestinal absorption is uncertain.
Accordingly, it would be of great therapeutic advantage to develop pharmaceutical compositions that enable self-administration by patients and administration to patients by non-medically trained persons outside of a hospital, clinic, ambulance, paramedical or similar medical settings and at the same time result in a sufficient treatment of a disorder requiring acute glucocorticoid therapy (e.g. acute adrenal crises) by providing a fast onset of action after administration. Moreover, there is also a need for pharmaceutical compositions that can be administered to a patient who e.g. is unconscious or otherwise unable to swallow a composition (e.g. a tablet or solution) and that does not require medically trained personnel or need be done in a medical setting.